Repeated dosing with the peroxisome proliferator clofibrate decreases the toxicity of model hepatotoxic agents in male mice1Presented in part at the at the 35th Annual Meeting of the Society of Toxicology, Anaheim, CA, 1996.1

Manautou, José E.; Silva, Vanessa M.; Hennig, Gayle E.; Whiteley, Herbert E.

doi:10.1016/s0300-483x(98)00013-4

Cited by 39 publications

(24 citation statements)

References 26 publications

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“…Paraffin-embedded kidney sections (5 m) were stained with hematoxylin and eosin and examined for histopathologic changes by a board-certified veterinary pathologist according to a published grading scale (Manautou et al, 1998). Neutrophils were counted from five to nine mice per group in three nonoverlapping fields at 40ϫ magnification.…”

Section: Methodsmentioning

confidence: 99%

Transcriptional Regulation of Renal Cytoprotective Genes by Nrf2 and Its Potential Use as a Therapeutic Target to Mitigate Cisplatin-Induced Nephrotoxicity

Aleksunes

Goedken²,

Rockwell

et al. 2010

J Pharmacol Exp Ther

156

109

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The use of the chemotherapeutic drug cisplatin is limited in part by nephrotoxicity. Cisplatin causes renal DNA adducts and oxidative stress in rodents. The transcription factor Nrf2 (nuclear factor E2-related factor 2) induces expression of cytoprotective genes, including Nqo1 (NADPH:quinone oxidoreductase 1), Ho-1 (heme oxygenase-1), and Gclc (glutamate cysteine ligase catalytic subunit), in response to electrophilic and oxidative stress. In the present study, plasma and kidneys from wild-type and Nrf2-null mice were collected after receiving cisplatin for evaluation of renal injury, inflammation, mRNA, and protein expression. Compared with wild types, more extensive nephrotoxicity was observed in Nrf2-null mice after cisplatin treatment. Kidneys from Nrf2-null mice treated with cisplatin had more neutrophil infiltration accompanied by increased p65 nuclear factor B binding and elevated inflammatory mediator mRNA levels. Cisplatin increased renal mRNA and protein expression of cytoprotective genes (Nqo1, Ho-1, Gclc) and transporters Mrp2 and Mrp4 in wild-type but not in Nrf2-null mice. Lastly, the Nrf2 activator, CDDO-Im [2-cyano-3,12-dioxooleana-1,9-dien-28-oic imidazolide], increased Nrf2 signaling in kidneys from wild-type mice and protected them from cisplatin toxicity. Collectively, these data indicate that the absence of Nrf2 exacerbates cisplatin renal damage and that pharmacological activation of Nrf2 may represent a novel therapy to prevent kidney injury. Coordinated regulation of detoxification enzymes and drug transporters and suppression of inflammation by Nrf2 during cisplatin nephrotoxicity are probable defense mechanisms to eliminate toxic mediators and promote proximal tubule recovery.

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Section: Methodsmentioning

confidence: 99%

Transcriptional Regulation of Renal Cytoprotective Genes by Nrf2 and Its Potential Use as a Therapeutic Target to Mitigate Cisplatin-Induced Nephrotoxicity

Aleksunes

Goedken²,

Rockwell

et al. 2010

J Pharmacol Exp Ther

156

109

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“…Embedded tissue was sectioned, stained with H&E or by the Yasue histochemical method (35) for detecting calcium oxalate crystals, and examined by light microscopy. Liver sections were scored blinded to genotype for the severity of degeneration and necrosis using a 0-5 scale as previously described (36).…”

Section: Figurementioning

confidence: 99%

Urolithiasis and hepatotoxicity are linked to the anion transporter Sat1 in mice

Dawson

Russell²,

Lee³

et al. 2010

J. Clin. Invest.

104

127

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Urolithiasis, a condition in which stones are present in the urinary system, including the kidneys and bladder, is a poorly understood yet common disorder worldwide that leads to significant health care costs, morbidity, and work loss. Acetaminophen-induced liver damage is a major cause of death in patients with acute liver failure. Kidney and urinary stones and liver toxicity are disturbances linked to alterations in oxalate and sulfate homeostasis, respectively. The sulfate anion transporter-1 (Sat1; also known as Slc26a1) mediates epithelial transport of oxalate and sulfate, and its localization in the kidney, liver, and intestine suggests that it may play a role in oxalate and sulfate homeostasis. To determine the physiological roles of Sat1, we created Sat1 -/-mice by gene disruption. These mice exhibited hyperoxaluria with hyperoxalemia, nephrocalcinosis, and calcium oxalate stones in their renal tubules and bladder. Sat1 -/-mice also displayed hypersulfaturia, hyposulfatemia, and enhanced acetaminophen-induced liver toxicity. These data suggest that Sat1 regulates both oxalate and sulfate homeostasis and may be critical to the development of calcium oxalate urolithiasis and hepatotoxicity.

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“…15 The liver is a major site of biotransformation and is critical in modulating chemical and metabolically induced toxicity, and there is evidence suggesting that PPARs may modulate hepatotoxicity. Pretreatment of mice with the PPAR␣ ligand clofibrate protects against carbon tetrachloride-induced hepatotoxicity 16,17 and attenuates acetaminophen-induced hepatotoxicity in wildtype mice but not in PPAR␣-null mice. 18 This indicates that the protective effects of clofibrate are PPAR␣ dependent.…”

mentioning

confidence: 99%

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

et al. 2008

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Potential functional roles for the peroxisome proliferator-activated receptor-␤/␦ (PPAR␤/␦) in skeletal muscle fatty acid catabolism and epithelial carcinogenesis have recently been described. Whereas PPAR␤/␦ is expressed in liver, its function in this tissue is less clear. To determine the role of PPAR␤/␦ in chemically induced liver toxicity, wild-type and PPAR␤/␦-null mice were treated with azoxymethane (AOM) and markers of liver toxicity examined. Bile duct hyperplasia, regenerative hyperplasia, and increased serum alanine aminotransferase (ALT) were found in AOM-treated PPAR␤/␦-null mice, and these effects were not observed in similarly treated wild-type mice. Exacerbated carbon tetrachloride (CCl 4 ) hepatoxicity was also observed in PPAR␤/␦-null as compared with wild-type mice. No differences in messenger RNAs (mRNAs) encoding cytochrome2E1 required for the metabolic activation of AOM and CCl 4 were observed between wild-type or PPAR␤/␦-null mice in response to CCl 4 . Significant differences in the expression of genes reflecting enhanced nuclear factor kappa B (NF-B) activity were noted in PPAR␤/␦-null mice. Conclusion:Results from these studies show that PPAR␤/␦ is protective against liver toxicity induced by AOM and CCl 4 , suggesting that this receptor is hepatoprotective against environmental chemicals that are metabolized in this tissue. (HEPATOLOGY 2008;47:225-235.)

show abstract

Repeated dosing with the peroxisome proliferator clofibrate decreases the toxicity of model hepatotoxic agents in male mice1Presented in part at the at the 35th Annual Meeting of the Society of Toxicology, Anaheim, CA, 1996.1

Cited by 39 publications

References 26 publications

Transcriptional Regulation of Renal Cytoprotective Genes by Nrf2 and Its Potential Use as a Therapeutic Target to Mitigate Cisplatin-Induced Nephrotoxicity

Transcriptional Regulation of Renal Cytoprotective Genes by Nrf2 and Its Potential Use as a Therapeutic Target to Mitigate Cisplatin-Induced Nephrotoxicity

Urolithiasis and hepatotoxicity are linked to the anion transporter Sat1 in mice

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

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